Discovery of a Clinical Candidate from the Structurally Unique Dioxa-bicyclo[3.2.1]octane Class of Sodium-Dependent Glucose Cotransporter 2 Inhibitors
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- 作者：Vincent Mascitti ; Tristan S. Maurer ; Ralph P. Robinson ; Jianwei Bian ; Carine M. Boustany-Kari ; Thomas Brandt ; Benjamin M. Collman ; Amit S. Kalgutkar ; Michelle K. Klenotic ; Michael T. Leininger ; Andre虂 Lowe ; Robert J. Maguire ; Victoria M. Masterson ; Zhuang Miao ; Emi Mukaiyama ; Jigna D. Patel ; John C. Pettersen ; Cathy Pre虂ville ; Brian Samas ; Li She ; Zhanna Sobol ; Claire M. Steppan ; Benjamin D. Stevens ; Benjamin A. Thuma ; Meera Tugnait ; Dongxiang Zeng ; Tong Zhu
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：April 28, 2011
- 年：2011
- 卷：54
- 期：8
- 页码：2952-2960
- 全文大小：996K
- 年卷期：v.54,no.8(April 28, 2011)
- ISSN：1520-4804
文摘
Compound 4 (PF-04971729) belongs to a new class of potent and selective sodium-dependent glucose cotransporter 2 inhibitors incorporating a unique dioxa-bicyclo[3.2.1]octane (bridged ketal) ring system. In this paper we present the design, synthesis, preclinical evaluation, and human dose predictions related to 4. This compound demonstrated robust urinary glucose excretion in rats and an excellent preclinical safety profile. It is currently in phase 2 clinical trials and is being evaluated for the treatment of type 2 diabetes.